Sorting nexin 1 loss results in increased oxidative stress and hypertension

Jian Yang, Laureano D. Asico, Amber L. Beitelshees, Jun B. Feranil, Xiaoyan Wang, John E. Jones, Ines Armando, Santiago G. Cuevas, Gary L. Schwartz, John G. Gums, Arlene B. Chapman, Stephen T. Turner, Eric Boerwinkle, Rhonda M. Cooper-DeHoff, Julie A. Johnson, Robin A. Felder, Edward J. Weinman, Chunyu Zeng, Pedro A. Jose, Van Anthony M. Villar

Research output: Contribution to journalArticle

Abstract

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1−/− mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1R), NADPH oxidase (NOX) subunits, D5R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Original languageEnglish (US)
Pages (from-to)7941-7957
Number of pages17
JournalFASEB Journal
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2020

Keywords

  • dopamine D receptor
  • hypertension
  • oxidative stress
  • renal proximal tubule cells
  • sorting nexin 1

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Yang, J., Asico, L. D., Beitelshees, A. L., Feranil, J. B., Wang, X., Jones, J. E., Armando, I., Cuevas, S. G., Schwartz, G. L., Gums, J. G., Chapman, A. B., Turner, S. T., Boerwinkle, E., Cooper-DeHoff, R. M., Johnson, J. A., Felder, R. A., Weinman, E. J., Zeng, C., Jose, P. A., & Villar, V. A. M. (2020). Sorting nexin 1 loss results in increased oxidative stress and hypertension. FASEB Journal, 34(6), 7941-7957. https://doi.org/10.1096/fj.201902448R